Migraine headache afflicts 15-20% of the population and is a major cause of economic loss. Despite its high prevalence and serious economic consequences, its neurophysiological, metabolic and molecular basis remain poorly understood and under investigated. This application represents a joint effort by basic and clinical neuroscientists to understand the biological basis of migraine headache. Our program, comprised of three (3) multi-disciplinary projects plus Scientific and Administrative Cores, aims to achieve a greater understanding of the migraine aura and headache. One project will address the consequences of the migraine visual and somatosensory aura on metabolism and neurophysiological function. The aura, often the most troublesome, and not infrequently the only symptom of migraine, may persist and very infrequently progresses to cerebral infarct. This project will use multi-modality fMRI imaging techniques to understand whether the aura has an underlying neurophysiological and metabolic signature and whether particular sub-regions of visual cortex are unusually susceptible and serve as initiators to subsequent propagating BOLD signal changes. One project proposes experiments to better understand headache and the role of sensitization within primary afferents, trigeminal nucleus caudalis and thalamus. Functional imaging will serve as the basis for this aim as well. Because we believe that migraine is accompanied by meningeal events which lead to trigemino-vascular activation and the headache, this project will address the genesis of headache and the importance of nitric oxide using intravenous infusion of the nitric oxide donor, nitroglycerin, in rats, as a novel animal model. Our preliminary data support the idea that nitroglycerin infusion promotes the upregulation of inflammatory and cytokine genes within the meninges. Studies are proposed to examine the importance of oxidative and nitrergic stress leading to iNOS induction in specific dural cell populations and the importance of transcriptional mechanisms, in the interest of migraine pathophysiology and the development of new therapies.